Harnessing IDO inhibitors to optimize cancer immunotherapy

The tumor microenvironment (TME) is rich in immunosuppressive molecules that collectively hinder effective anti-tumor immune responses and promote tumor progression. Among the most prominent are transforming growth factor-beta (TGF-β), which suppresses T cell proliferation, promotes the differentiation of regulatory T cells, and remodels the extracellular matrix to exclude immune cells. Enzymes such as indoleamine 2,3-dioxygenase 1 and 2 (IDO1, IDO2) and tryptophan 2,3-dioxygenase (TDO) degrade tryptophan into kynurenine metabolites, leading to T cell anergy, apoptosis, and expansion of regulatory T cells through activation of the aryl hydrocarbon receptor. Recently, cancer immunotherapy has seen remarkable progress with the advent of IDO inhibitors, which target a critical pathway through which tumors evade immune responses to their advantage. This review outlines the mechanisms by which IDO contributes to tumor-induced immune suppression, examining the associated signaling pathways that facilitate this process. It thoroughly reviews the potential of IDO inhibitors as monotherapy or in combination with conventional chemotherapy, assessing their clinical implications and safety profiles. The discussion includes perspectives on overcoming resistance mechanisms and optimizing therapeutic outcomes through combination strategies. Ultimately, this document aims to enhance the understanding of IDO's role in cancer immunopathogenesis, advancing patient management within the oncological landscape.